Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

[Coverage rate of influenza vaccine in healthcare workers in the 12 cystic fibrosis centres of the Greater South Region of France in 2005/2006]. / Couverture vaccinale vis-à-vis de la grippe des soignants des douze Centres de Ressources et de Compétences de la Mucoviscidose du Grand-Sud de la France en 2005-2006.

INTRODUCTION: In France annual influenza vaccination is recommended for healthcare workers but few data regarding coverage are available. The objective of the present study was to evaluate influenza vaccine coverage rate in healthcare workers from the 12 cystic fibrosis centres in the Greater South Region of France during the 2005/2006 'flu season. METHODS: An observational, descriptive telephone survey was performed from February to April 2006 to collect information about the vaccine status of all the healthcare workers in the 12 cystic fibrosis centres of the Muco-Sud and Muco-Med networks. RESULTS: During the 2005/2006 'flu season a 59.4% influenza vaccine coverage rate was achieved in the 128 healthcare workers. The influenza vaccine coverage rate ranged from 81.4% (physicians) to 16.7% (social workers). Vaccination was usually performed in October (42.1%) or November (39.5%) by occupational medicine officers (65.8%). The most frequently reported reason for non-vaccination was "vaccine useless as the disease is benign" (36.7%). CONCLUSIONS: The influenza vaccine coverage rate in healthcare workers from the 12 cystic fibrosis centres in the Greater South Region of France is high, but still too low in view of the risks influenza may incur for cystic fibrosis patients. It fails to meet one of the objectives of French Public Health Law (at least 75% influenza vaccine coverage rate for healthcare workers by 2008).

[Adolescents with cystic fibrosis: the approach to transition from paediatric to adult care]. / Transition enfant-adulte au cours de la mucoviscidose.

Because of early and effective therapies, an increasing numbers of young people with cystic fibrosis (CF) reach adulthood. Preparing for and maintaining high quality CF care in the adult healthcare is critical for prolonged survival. Because adverse health consequences occur when inadequate transition arrangements are in place, safely transferring patients from pediatric to adult care is a priority. Key features include an early preparation, planning and self-management skills, a coordinated approach and a detailed communication between patients, families, pediatric and adult teams. Formal transition protocols and audits can support the process and be helpful for multidisciplinary teams.

[New therapies for cystic fibrosis targeting the CFTR gene or the CFTR protein]. / Nouvelles thérapeutiques de la mucoviscidose ciblant le gène ou la protéine CFTR.

BACKGROUND: The treatment of cystic fibrosis has been symptom-based for a number of years. New therapies that aim to improve CFTR protein function are now emerging. CURRENT SCIENTIFIC KNOWLEDGE: The results of gene therapy has been modest but a recent clinical trial shows a positive effect on FEV1. Recent research has focused primarily on CFTR protein function. Significant respiratory improvement (an average 10% FEV1 increase and a decrease in the frequency of exacerbations) has been achieved with ivacaftor, a CFTR potentiator, in patients with gating mutations, resulting in its marketing authorization (in 2012 for the G551D mutation and in 2015 for rarer mutations). In phe508del homozygous patients, the combination of ivacaftor with a CFTR corrector (lumacaftor) has also led to respiratory improvement, albeit less impressive. The effectiveness of ataluren in patients with nonsense mutations is being evaluated. OUTLOOK: New CFTR correctors and potentiators are being developed. CFTR protein therapy could change the course of the disease but cost/effectiveness issues should not be overlooked. CONCLUSION: Ivacaftor can be prescribed in CF patients with a class 3 mutation from the age of 6 years. The Orkambi® will soon be available for homozygous phe508del patients from the age of 12 years.

[New therapeutic developments in cystic fibrosis]. / Nouvelles thérapeutiques ciblant le canal chlorure dans la mucoviscidose.

Since the discovery of chloride secretion by the Cystic Fibrosis Transport regulator CFTR in 1983, and CFTR gene in 1989, knowledge about CFTR synthesis, maturation, intracellular transfer and function has dramatically expanded. These discoveries have led to the distribution of CF mutations into 6 classes with different pathophysiological mechanisms. In this article we will explore the state of art on CFTR synthesis and its chloride secretion function. We will then explore the consequences of the 6 classes of mutations on CFTR protein function and we will describe the new therapeutic developments aiming at correcting these defects.

Nasopharyngeal tuberculosis.

Rhinopharyngeal tuberculosis is a rare pathological condition. It is most often associated with lymph node and pulmonary lesions, but it may be an isolated finding. The authors report a recent case of an isolated rhinopharyngeal tuberculosis in a 64-year-old female. A review of the literature is presented. They emphasize the clinical presentation, that, in all aspects, may resemble a malignant tumour of the nasopharynx, as well as the difficulty of obtaining a pathological and bacteriological diagnosis.

[Influenza and asthma]. / Grippe et asthme.

The relationship between infections of the respiratory tract and exacerbations of pulmonary symptoms in individuals with asthma is well established on clinical grounds. Patients having an acute attack of asthma often give a history of a "cold" before the onset of the exacerbation. The identification rate of viruses during exacerbations of asthma (10-30%) is much higher than the viral identification rate generally found during asymptomatic periods in asthmatics (3%). The mechanisms whereby upper respiratory viruses might induce or contribute to attacks of asthma are currently unknown: epithelial damage, increased cytokines releasability, mouth breathing.... Influenza vaccination is recommended in patients with chronic pulmonary diseases. However, bronchial hyperreactivity has been reported after influenza vaccination in asthmatics. Reactions to these vaccines may be due to non-immunogenic impurities, which are not present in the more recently developed subunit vaccines. In spite of the lack of double-blind studies between subunit and killed influenza virus vaccines, and because of the potential bad prognosis of influenza infection on airway obstruction, influenza vaccination should be recommended in asthmatics with stable respiratory function but influenza vaccination rate remains low.

[Invasive pulmonary aspergillosis in 4 patients with acute decompensation of chronic respiratory insufficiency]. / Aspergillose pulmonaire invasive chez quatre patients en décompensation aiguë d'insuffisance respiratoire chronique.

Invasive pulmonary aspergillosis (API) is a necrotising pneumonia generally occurring in profoundly immunodepressed subjects. These observations were based on four patients in the intensive care unit, suffering from chronic respiratory failure (IRC), without profound immunodepression. After a pathophysiological and clinical review, a focus on the diagnostic methods permits one to stress on the reliability, in this type of patient, of the evidence from direct examination of aspergillus filaments in the bronchoalveolar lavage (LBA) or protected bronchial brushings, taking account of the weak value of routine culture of spit or bronchial aspiration in IRC in whom patients are frequently colonised. These four cases permit one to discuss the factors which predispose to the development of API outside the usual immune suppression: IRC itself, by the disorder of mucociliary function, which it leads to; repeated antibiotic therapy which destabilises the saprophytic flora; viral infections which would be responsible for transitory immunodepression. But it is above all steroid therapy which seems to be the major factor favouring the development of API without producing profound immunodepression but probably because it inhibits phagocytosis of aspergillus spores. In these circumstances it is necessary to make an early diagnosis and to use fibre optic bronchoscopy with protected sampling and bronchoalveolar lavage with a complete microbiological. Only early treatment allows one to contemplate a cure.

[Role of nocturnal oximetry in screening for sleep apnea syndrome in pulmonary medicine. Study of 329 patients]. / Place de l'oxymétrie nocturne dans le dépistage du syndrome d'apnée du sommeil en milieu pneumologique. Etude de 329 patients.

Nocturnal oximetry can show nocturnal oxygen desaturation. This examination was proposed as an investigation for the early detection of the sleep apnoea syndrome (SAS). We have compared the results of nocturnal oximetry and polysomnography in 329 consecutive patients seen in the department of thoracic medicine for the early detection of the SAS between June 1990 and June 1995. The diagnosis of SAS was confirmed at the time of polysomnography using an hypopnoea/apnoea index (IAH) greater or equal to 15 per hour. Two parameters of oximetry were well correlated with IAH less than 15 per hour: if the mean oxygen saturation is greater than 92% and for less than five per cent of the time of the examination there was a saturation of less than 90%. The sensitivity was 89.7% and the specificity was 57.8%. Among the 48 false positive cases on oximetry 17 patients were found to be suffering from COPD and 31 patients were probably suffering from a syndrome of upper airways resistance or possibly from the hypoventilation obesity syndrome. Amongst the 22 false, negatives to oximetry 10 non COPD patients with an IAH of greater than 30 per hour and diurnal somnolence had important anomalies of the oro-pharyngeal pathway as the origin of their nocturnal apnoea. The 12 other false negatives were patients with moderate SAS with an IAH of between 15 and 20 per hour. Logistical analysis has shown the association of the two oximetric criteria (mean oxygen saturation or percentage of time with a saturation of less than 5%) with clinical criteria (body mass index and formation on diurnal somnolence from a questionnaire) would enable a probable diagnosis of SAS in 75% of cases. Our study shows that nocturnal oximetry used an early diagnosis test, associated with clinical and respiratory function data enables the number of requests for polysomnography to be reduced.

[Results of 248 patients with sleep apnea syndrome treated by continuous positive pressure ventilation between 1990 and 1995. A study of compliance and outcome of the apnea-hypopnea index]. / Suivi de 248 patients présentant un syndrome d'apnée du sommeil traités par pression positive continue entre 1990 et 1995. Etude de l'observance et du devenir de l'index d'apnée-hypopnée.

Between 1990 and 1995, 369 patients were investigated for obstructive sleep apnea syndrome (OSAS) by polysomnography. Among them, 248 patients with a mean Apnea-Hyponea index (AHI) of 37.7 per hour were treated by nasal continuous positive airway pressure (n-CPAP). Mean follow up was 39.5 +/- 20.4 months. In this group, 23 patients (9.2%) refused nCPAP immediately or after the first night and 39 (15.7%) gave up later. 15 patients (6%) died during the period of the study. The cumulative compliance reached 70% at 72 months. Non compliant patients usually gave up n-CPAP before the end of the first year. We compared the group of 150 patients always treated at the date of 31/12/95 with the group of 62 patients who refused nCPAP initially or gave up later. There was no difference in clinical parameters or polysomnographic data between the two groups. In 94 patients treated by nCPAP for more than a year we evaluated the outcome of AHI by a polysomnography performed after 72 hours of nCPAP cessation. Mean AHI of the group at this time was 38.2 +/- 20.3/h and was well correlated with the initial index (r = 0.41, p < 0.0001). However for 28 patients (29.7%) we observed, at the time of this second AHI determination, a variation (plus or minus) of at least 50% of the index. 6 patients, without any significative weigth loss, had an AHI below 5/h at this second determination. In this small group nCPAP was interrupted for 6 to 12 months, then another polysomnography was performed. At this time mean AHI was 42.4/h and clinical symptoms had reappeared in all patients. This study demonstrated that compliance to nCPAP in OSAS patients is good. No clinical or polysomnographic factors allow to predict non compliance. AHI is not modified by long term treatment with nCPAP.

Substance P and alveolar macrophages: effects on oxidative metabolism and eicosanoid production.

The tachykinin substance P (SP) is present in lung sensory nerve endings and may be released after neurogenic stimulation. Its role in the pathogenesis of asthma is still unclear. Nevertheless, it may play a major role in airway neurogenic inflammation. Alveolar macrophages are the predominant cells of the airway space and are involved in various types of airway inflammation. We studied guinea pig alveolar macrophage response to SP and other related peptide (C- and N-terminal sequences, NK1-receptor agonist) stimulation. Alveolar guinea pig macrophages were recovered by bronchoalveolar lavage (BAL). Macrophage reactive oxygen intermediate (ROI) production was studied by luminol-dependent chemiluminescence with several concentrations of SP and related peptides. Eicosanoid synthesis after stimulation was evaluated by thin-layer chromatography (TLC) and enzyme-linked immunosorbent assay (ELISA). SP, C-terminal sequence, and NK1-receptor agonist significantly increased ROI production by alveolar macrophages (P < 0.01). NK1-agonist and C-terminal sequence modified arachidonic acid metabolism and induced a significant increase in prostaglandin (PG)D2 synthesis (211% and 66%, respectively). We concluded that SP and related peptides directly affect guinea pig alveolar macrophages by inducing the production of inflammatory metabolites.

Comparison of efficacy and safety of cetirizine and ebastine in patients with perennial allergic rhinitis.

BACKGROUND: Cetirizine and ebastine are two second-generation histamine H1 antagonists undergoing evaluation for treatment of perennial rhinitis. OBJECTIVE: The clinical efficacy and safety of once daily cetirizine 10 mg were compared with ebastine 10 mg in patients with perennial allergic rhinitis in a 4-week, double-blind, parallel-group, randomized, multicenter study. METHOD: Two hundred fourteen patients (120 females, 94 males, aged 17 to 70 years, mean 31.2 years) were selected on the basis of perennial allergic rhinitis history, positive skin test for perennial allergens and a minimum rhinitis symptom score of 6/12. Patients recorded nasal symptom severity (nasal stuffiness, nasal discharge, sneezing, and itching) once daily on diary cards using a rating scale of 0 (none) to 3 (severe). Clinicians made an overall evaluation after 4 weeks of treatment. An intent-to-treat-analysis was performed comparing cetirizine (106 patients) and ebastine groups (108 patients). RESULTS: The individual and total baseline symptom scores were comparable in both treatment groups. During the first week, the percentage mean decrease in the total nasal symptom score from baseline (sum of nasal stuffiness, discharge, sneezing, and itching) was significantly higher for cetirizine 46.2% than for ebastine 32.8% (P = .037). After 4 weeks of treatment, total symptom score improvement was 53.7% for cetirizine and 44.7% for ebastine (P = .12), and the clinician's overall evaluation showed that the percentage of symptom-free patients was significantly higher for cetirizine 17.8% than for ebastine 6.9% (P = .02). Cetirizine also significantly improved nasal stuffiness. An associated antiinflammatory effect is suggested. Commonly reported drug-related side effects were similar in both groups. CONCLUSION: This study shows that both antihistamines, cetirizine 10 mg and ebastine 10 mg once a day, improved symptom scores of patients with perennial allergic rhinitis. Cetirizine, however, provided faster improvement and total relief in a greater number of patients after 4 weeks.